The human beta-globin locus control region (LCR) is a powerful chromosome organizational and regulatory entity and is required for both chromatin remodeling as well as for optimal expression of globin genes during erythroid development. Dr. Bungert has recently shown through analysis of germ line YAC-transformed transgenic animals that the dominant regulatory domain controlling the activity of all of the human beta-locus genes (LCR) throughout development is a single functional genetic entity. In the first specific aim, he proposes to analyze individual hypersensitive site mutations within the human beta-globin LCR and to examine the consequences of these mutations on human beta-globin locus gene activation after the mutant YACs are incorporated into germ line transgenic mice. In the second specific aim, he proposes to initiate a detailed structure/function analysis of the active LCR.